This is the resubmission of the competitive renewal of our RO1 that generated >63 publications over a 12-year funding period. Our goal is to assess the impact of dietary factors on chronic inflammation (INFL) profiles associated with cardiovascular disease (CVD) in treated and untreated SIV infections. As reported in other clinical conditions, diet plays a key role in modulating gut INFL, epithelial integrity and microbial translocation through shifts in microbiota metabolites, which may also induce excessive cell proliferation and activation or a skewed cell differentiation, resulting in a reduction of the immune cell subsets critical for gut health. Diet-induced changes in the host cellular fat and sugar metabolism may enhance SIV/HIV replication, reduce immune cell responses and promote cell senescence. Certain diets thus have the potential to enhance gut dysfunction during SIV/HIV infection. In addition to the impact on the gut, the diet-induced changes in microbiota may trigger changes in the adipose tissue that promote systemic INFL and induce liver damage that may associate abnormal clearance of microbial products, antiretroviral (ARV) metabolism and coagulation factor synthesis. Our hypothesis is therefore that, in the context of HIV/SIV, the diet?microbiota?metabolite axis has a critical impact on IA/INFL, response to ART and development of CVD. Long-term, perfectly controlled diet studies are very difficult to carry out in HIV+ infected subjects and can be confounded by numerous other factors (i.e., ART, age, alcohol, drugs, smoking, lack of physical activity) that may affect the same metabolic pathways. Our preliminary data show that administration of a high fat diet to SIV-infected NHPs induced alterations in the gut microbiota, MT, nonalcoholic fatty liver and increases in systemic IA/INFL, which altogether resulted in a significantly decreased survival. Based on these preliminary data and the rationales above, and as a logical continuation of the research from the previous funding periods, we designed this project, aimed at assessing the impact of major dietary components on the natural history of SIV infection and the development of SIV-related CVD in ART-nave NHPs and chronically infected NHPs on ART. In an NHP model developed in our lab, that faithfully reproduces the CVD described in HIV+ subjects, we will perform controlled studies to test the long term effects of multiple diets prior and after SIV infection, on or off ART. These experiments will establish the pathways impacted by each dietary component and cannot be performed in HIV+ subjects due to the difficulty to maintain strict diets, the risks associated with certain diets that can produce harm, and to the impossibility to perform extensive invasive sampling. Our goal is to develop a permanent drug-free, no risk adjuvant therapy for HIV+ subjects, to reduce residual INFL, improve immune function and decrease the CV comorbidities. If successful, these highly translational experiments may improve clinical management and survival of HIV+ patients, without the risk of adding new drug interactions in this heavily medicated population.